Publications
976 results found
Khongkow P, Karunarathna U, Khongkow M, et al., 2013, FOXM1 targets NBS1 to regulate DNA damage-induced senescence and epirubicin resistance, Oncogene, Vol: 33, Pages: 4144-4155, ISSN: 1476-5594
FOXM1 is implicated in genotoxic drug resistance but its mechanism of action remains elusive. We show here that FOXM1-depletion can sensitize breast cancer cells and mouse embryonic fibroblasts (MEFs) into entering epirubicin-induced senescence, with the loss of long-term cell proliferation ability, the accumulation of γH2AX foci, and the induction of senescence-associated β-galactosidase activity and cell morphology. Conversely, reconstitution of FOXM1 in FOXM1-deficient MEFs alleviates the accumulation of senescence-associated γH2AX foci. We also demonstrate that FOXM1 regulates NBS1 at the transcriptional level through an forkhead response element on its promoter. Like FOXM1, NBS1 is overexpressed in the epirubicin-resistant MCF-7EpiR cells and its expression level is low but inducible by epirubicin in MCF-7 cells. Consistently, overexpression of FOXM1 augmented and FOXM1 depletion reduced NBS1 expression and epirubicin-induced ataxia-telangiectasia mutated (ATM)phosphorylation in breast cancer cells. Together these findings suggest that FOXM1 increases NBS1 expression and ATM phosphorylation, possibly through increasing the levels of the MRN(MRE11/RAD50/NBS1) complex. Consistent with this idea, the loss of P-ATM induction by epirubicin in the NBS1-deficient NBS1-LBI fibroblasts can be rescued by NBS1 reconstitution. Resembling FOXM1, NBS1 depletion also rendered MCF-7 and MCF-7EpiR cells more sensitive to epirubicin-induced cellular senescence. In agreement, the DNA repair-defective and senescence phenotypes in FOXM1-deficent cells can be effectively rescued by overexpression of NBS1. Moreover, overexpression of NBS1 and FOXM1 similarly enhanced and their depletion downregulated homologous recombination (HR) DNA repair activity. Crucially, overexpression of FOXM1 failed to augment HR activity in the background of NBS1 depletion, demonstrating that NBS1 is indispensable for the HR function of FOXM1. The physiological relevance of the regulation o
Page K, Guttery DS, Zahra N, et al., 2013, Influence of Plasma Processing on Recovery and Analysis of Circulating Nucleic Acids, PLOS ONE, Vol: 8, ISSN: 1932-6203
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- Citations: 136
Eccles SA, Aboagye EO, Ali S, et al., 2013, Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer, Breast Cancer Research, Vol: 15, Pages: R-R, ISSN: 1465-542X
IntroductionBreast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice.MethodsMore than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer ‘stem’ cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account.ResultsThe 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease
Kaliszczak M, Patel H, Kroll SHB, et al., 2013, Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance, British Journal of Cancer, Vol: 109, Pages: 2356-2367, ISSN: 1532-1827
background: Cyclin-dependent kinases (CDKs) control cell cycle progression, RNA transcription and apoptosis, making them attractive targets for anticancer drug development. Unfortunately, CDK inhibitors developed to date have demonstrated variable efficacy.methods: We generated drug-resistant cells by continuous low-dose exposure to a model pyrazolo[1,5-a]pyrimidine CDK inhibitor and investigated potential structural alterations for optimal efficacy.results: We identified induction of the ATP-binding cassette (ABC) transporters, ABCB1 and ABCG2, in resistant cells. Assessment of features involved in the ABC transporter substrate specificity from a compound library revealed high polar surface area (>100 Å2) as a key determinant of transporter interaction. We developed ICEC-0782 that preferentially inhibited CDK2, CDK7 and CDK9 in the nanomolar range. The compound inhibited phosphorylation of CDK substrates and downregulated the short-lived proteins, Mcl-1 and cyclin D1. ICEC-0782 induced G2/M arrest and apoptosis. The permeability and cytotoxicity of ICEC-0782 were unaffected by ABC transporter expression. Following daily oral dosing, the compound inhibited growth of human colon HCT-116 and human breast MCF7 tumour xenografts in vivo by 84% and 94%, respectively.conclusion: We identified a promising pyrazolo[1,5-a]pyrimidine compound devoid of ABC transporter interaction, highly suitable for further preclinical and clinical evaluation for the treatment of cancer.
Challapalli A, Kenny LM, Hallett WA, et al., 2013, <SUP>18</SUP>F-ICMT-11, a Caspase-3-Specific PET Tracer for Apoptosis: Biodistribution and Radiation Dosimetry, JOURNAL OF NUCLEAR MEDICINE, Vol: 54, Pages: 1551-1556, ISSN: 0161-5505
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- Citations: 75
Benzonana LL, Perry NJS, Watts HR, et al., 2013, Isoflurane, a Commonly Used Volatile Anesthetic, Enhances Renal Cancer Growth and Malignant Potential <i>via</i> the Hypoxia-inducible Factor Cellular Signaling Pathway <i>In Vitro</i>, ANESTHESIOLOGY, Vol: 119, Pages: 593-605, ISSN: 0003-3022
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- Citations: 149
Stebbing J, Filipovic A, Lit LC, et al., 2013, LMTK3 is implicated in endocrine resistance via multiple signaling pathways, ONCOGENE, Vol: 32, Pages: 3371-3380, ISSN: 0950-9232
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- Citations: 35
Bhangu A, Beynon J, Brown G, et al., 2013, Consensus statement on the multidisciplinary management of patients with recurrent and primary rectal cancer beyond total mesorectal excision planes, BRITISH JOURNAL OF SURGERY, Vol: 100, Pages: E1-E33, ISSN: 0007-1323
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- Citations: 185
Coombes RC, Cardoso F, Isambert N, et al., 2013, A phase I dose escalation study to determine the optimal biological dose of irosustat, an oral steroid sulfatase inhibitor, in postmenopausal women with estrogen receptor-positive breast cancer, BREAST CANCER RESEARCH AND TREATMENT, Vol: 140, Pages: 73-82, ISSN: 0167-6806
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- Citations: 28
Khongkow M, Olmos Y, Gong C, et al., 2013, SIRT6 modulates paclitaxel and epirubicin resistance and survival in breast cancer, CARCINOGENESIS, Vol: 34, Pages: 1476-1486, ISSN: 0143-3334
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- Citations: 121
Guttery DS, Blighe K, Page K, et al., 2013, Hide and seek: tell-tale signs of breast cancer lurking in the blood, CANCER AND METASTASIS REVIEWS, Vol: 32, Pages: 289-302, ISSN: 0167-7659
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- Citations: 12
Saleem A, Searle G, Kenny LM, et al., 2013, Brain and tumor penetration of carbon-11-labeled lapatinib ([<SUP>11</SUP>C]Lap) in patients (pts) with HER2-overexpressing metastatic breast cancer (MBC), 49th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X
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- Citations: 2
Stebbing J, Payne R, Reise J, et al., 2013, The Efficacy of Lapatinib in Metastatic Breast Cancer with HER2 Non-Amplified Primary Tumors and EGFR Positive Circulating Tumor Cells: A Proof-Of-Concept Study, PLOS ONE, Vol: 8, ISSN: 1932-6203
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- Citations: 27
Lombardo Y, Filipovic A, Faronato M, et al., 2013, Role of nicastrin in the mediating chemoresistance of breast cancer cells, 104th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Faronato M, Lombardo Y, Filipovic A, et al., 2013, Anti-Nicastrin antibodies for the treatment of endocrine resistant breast cancer., 104th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Pellegrino L, Stebbing J, Braga VM, et al., 2013, miR-23b regulates cytoskeletal remodeling, motility and metastasis by directly targeting multiple transcripts, Nucleic Acids Research, Vol: 41, Pages: 5400-5412, ISSN: 1362-4962
Uncontrolled cell proliferation and cytoskeletal remodeling are responsible for tumor development and ultimately metastasis. A number of studies have implicated microRNAs in the regulation of cancer cell invasion and migration. Here, we show that miR-23b regulates focal adhesion, cell spreading, cell-cell junctions and the formation of lamellipodia in breast cancer (BC), implicating a central role for it in cytoskeletal dynamics. Inhibition of miR-23b, using a specific sponge construct, leads to an increase of cell migration and metastatic spread in vivo, indicating it as a metastatic suppressor microRNA. Clinically, low miR-23b expression correlates with the development of metastases in BC patients. Mechanistically, miR-23b is able to directly inhibit a number of genes implicated in cytoskeletal remodeling in BC cells. Through intracellular signal transduction, growth factors activate the transcription factor AP-1, and we show that this in turn reduces miR-23b levels by direct binding to its promoter, releasing the pro-invasive genes from translational inhibition. In aggregate, miR-23b expression invokes a sophisticated interaction network that co-ordinates a wide range of cellular responses required to alter the cytoskeleton during cancer cell motility.
Long J, Delahanty RJ, Li G, et al., 2013, A Common Deletion in the <i>APOBEC3</i> Genes and Breast Cancer Risk, JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, Vol: 105, Pages: 573-579, ISSN: 0027-8874
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- Citations: 109
Coombes RC, Tat T, Miller ML, et al., 2013, An open-label study of lapatinib in women with HER-2-negative early breast cancer: the lapatinib pre-surgical study (LPS study), ANNALS OF ONCOLOGY, Vol: 24, Pages: 924-930, ISSN: 0923-7534
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- Citations: 13
Shaw JA, Blighe K, Page K, et al., 2013, Determination of Breast Cancer Dormancy: Analysis of Circulating Free DNA Using SNP 6.0 Arrays, Tumor Dormancy, Quiescence, and Senescence, Editors: Hayat, Publisher: Springer, ISBN: 9789400759572
New biomarkers are needed in breast cancer to monitor minimal residual disease. Specific point mutations, promoter methylation and loss of heterozygosity have been demonstrated previously in paired tumor and circulating cell-free DNA (cfDNA) isolated from plasma. Moreover, acquired alterations unique to cfDNA have also been found, suggesting disease progression. This prompted us to characterize the “circulating” breast cancer genome, thus testing the hypothesis that cfDNA acts as a surrogate liquid biopsy of breast cancer. This was achieved using Affymetrix SNP 6.0 technology and bioinformatics to map single nucleotide polymorphism (SNP) and copy number variation (CNV), comparing cfDNA with matched normal leucocyte and primary tumor DNA in breast cancer patients and paired normal leucocytes and cfDNA in healthy female controls. Our results show that concordance of SNP genotype calls in paired leucocytes and cfDNA can distinguish between primary breast cancer patients and healthy controls (p < 0.0001), and between pre-surgical breast cancer patients and patients on follow-up after surgery and treatment (p = 0.0016). In 50 patients on follow-up, a significant difference (p = 0.0006) was seen between cfDNA samples taken an average of 3 years apart, suggesting disease progression. Considering CNVs, amplification was observed in matched tumor and cfDNA at multiple loci on different chromosome arms but was quiet or absent in normal DNA. Many of these tumor-specific CNVs contributed significantly to disease through binary logistic regression analysis. Furthermore these CNVs remained detectable in cfDNA up to 12 years after diagnosis and treatment despite no other evidence of disease. Taken together these cfDNA results suggest breast cancer dormancy in the majority of the patients on follow-up.
Lee B, Lim AK, Krell J, et al., 2013, The Efficacy of Axillary Ultrasound in the Detection of Nodal Metastasis in Breast Cancer, AMERICAN JOURNAL OF ROENTGENOLOGY, Vol: 200, Pages: W314-W320, ISSN: 0361-803X
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- Citations: 55
Bhangu A, Ali SM, Cunningham D, et al., 2013, Comparison of long-term survival outcome of operative vs nonoperative management of recurrent rectal cancer, COLORECTAL DISEASE, Vol: 15, Pages: 156-163, ISSN: 1462-8910
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- Citations: 33
Patten DK, Leff DR, Wani Z, et al., 2013, Is the presence of small volume disease in the sentinel node an indication for axillary clearance?, BREAST, Vol: 22, Pages: 70-73, ISSN: 0960-9776
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- Citations: 2
Raguz S, Adams C, Masrour N, et al., 2013, Loss of O-6-methylguanine-DNA methyltransferase confers collateral sensitivity to carmustine in topoisomerase II-mediated doxorubicin resistant triple negative breast cancer cells, Biochemical Pharmacology, Vol: 85, Pages: 186-196, ISSN: 0006-2952
Triple-negative breast cancer is characterized by aggressive tumours whose cells lack oestrogen and progesterone receptors and do not over-express HER2. It accounts for approximately 10–15% of breast cancer cases. We sought to generate a cellular model of chemotherapy drug resistance for this type of disease to provide the tools for the development of new therapies. Doxorubicin is a component of some chemotherapy regimes used to treat this form of cancer but resistance preventing disease eradication frequently occurs, mainly due to over-expression of drug transporters such as P-glycoprotein. CALDOX cells were generated by exposure of CAL51 to doxorubicin. Resistance to doxorubicin did not involve drug transporters, as the both parental and resistant cells accumulated doxorubicin to comparable levels. CALDOX cells had slower proliferation rate and an extended G1 cell cycle stage than the parental line, mainly due to an intrinsic activation of CDNK1 (p21), but this cell cycle block was not involved in the mechanism of resistance. CALDOX cells had reduced levels of TOP2A (topoisomerase IIα) and were cross resistant to the topoisomerase II inhibitors etoposide and mitoxantrone. CALDOX cells showed collateral sensitivity to carmustine due to the lack of O6-methylguanine-DNA-methyltransferase (MGMT) expression, related to the hypermethylation of its promoter. The collateral sensitivity of CALDOX cells to carmustine provides the rationale to evaluate MGMT promoter methylation status to design better therapeutic strategies for triple negative breast cancer.
Mallarkey G, Coombes RC, 2013, Targeted therapies in medical oncology: successes, failures and next steps, THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY, Vol: 5, Pages: 5-16, ISSN: 1758-8340
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- Citations: 8
Gao Q, Chang PL, Rueckert D, et al., 2013, Modeling of the bony pelvis from MRI using a multi-atlas AE-SDM for registrationand tracking in image-guided robotic prostatectomy, Computerized Medical Imaging and Graphics
Gao Q, Ali M, Edwards PE, 2013, AUTOMATED ATLAS-BASED PELVIMETRY USING HYBRID REGISTRATION, IEEE 10th International Symposium on Biomedical Imaging - From Nano to Macro (ISBI), Publisher: IEEE, Pages: 1292-1295, ISSN: 1945-7928
Zhang H, Lombardo Y, Filipovic A, et al., 2012, KSR1 is involved in functional interaction between p53 and BRCA1 and is an independent predictor of overall survival in breast cancer, CANCER RESEARCH, Vol: 72, ISSN: 0008-5472
Harada-Shoji N, Coombes RC, Lam EW-F, 2012, The role of RIP140 and FOXA1 in breast cancer endocrine sensitivity and resistance, CANCER RESEARCH, Vol: 72, ISSN: 0008-5472
Palmieri C, Rudraraju B, Abdel-Fatah TMA, et al., 2012, Expression of Phosphorylated Activating Transcription factor 2 (ATF2) is associated with sensitivity to endocrine therapy in breast cancer, CANCER RESEARCH, Vol: 72, ISSN: 0008-5472
Palmieri C, Gojis O, Rudraraju B, et al., 2012, Phosphorylation of Steroid Receptor Coactivator 3 (SRC3) at Ser543 is a novel independent prognostic marker in breast cancer, CANCER RESEARCH, Vol: 72, ISSN: 0008-5472
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